This document discusses the stability testing of drug-eluting stents. It outlines Conor's reservoir technology where the drug is formulated with a bio-resorbable polymer and deposited in wells on the stent struts. Tests discussed for ensuring stability include assays to measure drug content, identification and quantification of impurities and degradation products, in vitro drug release kinetics, polymer molecular weight and content, residual solvents, and particulate matter. The document recommends a stability protocol that includes testing samples from multiple batches at various time points under long-term and accelerated conditions to establish a shelf life for the drug-eluting stents.

1. Stability of Drug-
Eluting Stents
Mark A. Schreiber, Ph.D.
Director, Analytical Development
Conor Medsystems
CBI Stability
Conference
June 13, 2008

2. Outline
Overview
1.
Drug-Eluting Stents
2.
Conor’s Reservoir Technology
3.
Tests (chemical) applicable to stents
4.
Stability protocol design
5.
Summary/Conclusion
6.

3. Why Drug-Eluting Stents?
First Bare Metal Stent was implanted 1987

Set the stage for stents to be regulated by

CDRH (with review of CMC by CDER)
First DES approved in US (Cypher™) in 2003

Drug/polymer matrix is applied to a scaffold

that props the artery open.
Drug slowly elutes further reducing restenosis

In some cases, the remaining metal is

endothelialized in the arterial wall

4. Stent Reservoir Technology
Drug is formulated with bio-resorbable polymer

Solution is deposited in wells in the stent struts as a

solution
Solvent is evaporated, leaving drug/polymer matrix

Isolates the matrix from the stresses of insertion and

expansion.
Drug is slowly released as the polymer decomposes

(hydrolysis of ester linkages) and is absorbed
Directionality as well as the rate of drug release can

be controlled

5. Tests for DES’s
Appearance
Assay (Total Drug Load)
Impurities
Release Kinetics (Elution)
Residual Solvent
Polymer MW / Content
Particulates (USP)
LAL
Mechanical tests (not addressed here)

6. Sirolimus Chemical Structure

7. Assay
 HPLC method – composite of 5 stents
 Content on stent is <<1 mg (sum of
Isomers B&C)
 Sample volume is low to keep
concentration at acceptable level
 Sample directly injected without further
dilution

8. Impurities/Degradation Products
Thousands of isomers possible

HPLC – Size Exclusion Chromatography

(SEC)
Same sample solution as for assay

Impurity “monomers” are indistiguishable from

parent drug
Based on response of reference standard and

assay value, monomers are determined by
difference (average RRF)
Oligomers are separated and are quantitated

by normal area response calibration (RRF)

9. In Vitro Release
Desirable traits:
 Predicts the release of the drug in vivo
would be optimal and highly desirable
 Selected test should be simple, reliable,
and reproducible in order to be used for
QC purposes
 USP apparatus/special equipment

10. In Vitro Release (continued)
Define robustness of the method:

Release media composition

pH

Dips/flow rate

Temperature

Physical factors, e.g. stent orientation, stent diameter/

length
Demonstrate discrimination – determine lots that

should be rejected
As least 3 specification-sampling times covering

initial, middle, and terminal elution
Develop IVIVC, if possible


11. Conor Elution Method
USP 4 Apparatus, closed-loop recirculating

system
Media: Buffered Tween 20 / ACN, 50 mL/stent

7-hour release method

Method development performed to have in vitro

curve resemble in vivo release
Complete profile being determined in

development, with 3 specified timepoints
chosen: early (burst), middle, >80% release

12. In Vitro Release Curve
Cummulative Sirolimus Released (% )
100.00%
90.00%
80.00%
70.00%
60.00%
50.00%
40.00%
30.00%
20.00%
10.00%
0.00%
0 2 4 6 8
Time (hr)

13. Residual Solvent
 Solvent extraction
 GC with FID
 Solvent is difficult to remove below
~10% (w/w) relative to drug content
 Solvent can potentially affect release
kinetics
 Tested on release and stability

14. Polymer MW/Content
GPC Method with polystyrene stds / UV detection

Raw material controlled by Lactide/Glycolide ratio

and Inherent Viscosity (IV) of PLGA polymer
MW testing on raw material being performed to

develop correlation to IV
Product sterilization performed by e-beam, which

reduces MW by ~30%
Limited stability testing of MW on finished product

Polymer content controlled by drug/polymer ratio in

formulation.

15. Particulates
Sources: Formulation, stent platform, stent delivery

system, packaging, and environment.
Simulated use conditions should be employed in

testing
From Draft DES Guidance: “It is highly

recommended that particulate matter generation
over time be evaluated at each time point in the
stability protocol (instead of only at t=0 and
t=proposed expiration date). In the event that the
particle counts continually increase with aging or fail
to meet the acceptance criteria at the proposed
expiration date, additional data will be available to
support a shorter expiration date for the DES. “
Particle characterization and other considerations,

see draft guidance.

16. Stability Protocol
For establishment of shelf-life/expiration dating and

to support product stability for the duration of clinical
studies
Protocol can include appropriate bracketing and

matrixing designs as detailed in Guidance Document
Q1D. The protocol design should include the
extremes (in terms of both stent dimensions and total
drug load) as well as an intermediate size,
bracketing different stent designs.
“We recommend that stability testing include

samples from a minimum of three finished product
batches for each size tested.”

17. Stability Protocol (continued)

18. Stability Protocol (continued)
ICH recommended conditions including accelerated

are recommended.
Depending on the polymer being used, accelerated

may not be appropriate (Tg).
The following tests are recommended:

 Appearance
 Assay/drug content
 Impurities/degradation products
 In vitro drug release
 Particulate matter
 Sterility/package integrity at release, annually, &
expiration

19. Long Term (25 °C/60%RH) Stability
Testing Protocol
Time Points (months)
Tests Acceptance 0 3 6 9 12
Criteria*
Appearance X X X X X
Assay (drug X X X X X
content)
Impurities X X X X X
Individual
Total
Drug Release X X X X X
Particulate X X X X X
Matter
Endotoxins X X
Time Points (months)
*Same as regulatory specifications

20. Accelerated (40 °C/75%RH)
Stability Testing Protocol
Time Points (months)
Tests Acceptance 0 1 3 6
Criteria*
Appearance X X X X
Assay (drug content) X X X X
Impurities X X X X
Individual
Total
Drug Release X X X X
Time Points (months)
*Same as regulatory specifications

21. Stability Protocol (continued)
Real time, RT data should be used to establish a DES

shelf life. Depending on the quality of the data,
reasonable extrapolation of accelerated data may be
considered to assign shelf life.

22. Summary/Conclusion
Some testing is specific to the dosage form:

polymer characterization (MW, Tg),
particulate matter, residual solvents, elution
Review the draft guidance. You may have

specific circumstances in which a scientific
justification can be made for doing something
different, minimizing samples & studies.
Release and stability testing of Drug-Eluting

Stents similar to that of drugs with a different
controlled-release mechanism